Clinical Neurophysiology 126 (2015) 382–390

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The effects of transcranial direct current stimulation in patients with neuropathic pain from spinal cord injury Niran Ngernyam a,1, Mark P. Jensen f,2, Preeda Arayawichanon b, Narong Auvichayapat c,1, Somsak Tiamkao d, Suparerk Janjarasjitt e, Wiyada Punjaruk a, Anuwat Amatachaya a,1, Benchaporn Aree-uea a,1, Paradee Auvichayapat a,1,⇑ a

Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002 Thailand Department of Rehabilitation Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002 Thailand Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002 Thailand d Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002 Thailand e Department of Electrical and Electronic Engineering, Faculty of Engineering, UbonRatchathani University, UbonRatchathani, 34190 Thailand f Department of Rehabilitation Medicine, University of Washington, Seattle, USA b c

a r t i c l e

i n f o

Article history: Accepted 22 May 2014 Available online 21 June 2014 Keywords: Transcranial direct current stimulation Electroencephalogram EEG spectral analysis Spinal cord injury Neuropathic pain

h i g h l i g h t s  A single session of transcranial direct current stimulation (tDCS) over the left motor area significantly

reduces neuropathic pain associated with spinal cord injury (SCI-related NP).  After tDCS in patients with SCI-related NP, peak frequency in the theta–alpha frequency (PTAF)

increased under the area of stimulated site.  Increased left anterior PTAF may be associated with reduced pain intensity.

a b s t r a c t Objective: Transcranial direct current stimulation (tDCS) has demonstrated efficacy for reducing neuropathic pain, but the respective mechanisms remain largely unknown. The current study tested the hypothesis that pain reduction with tDCS is associated with an increase in the peak frequency spectrum density in the theta–alpha range. Methods: Twenty patients with spinal cord injury and bilateral neuropathic pain received single sessions of both sham and anodal tDCS (2 mA) over the left primary motor area (M1) for 20 min. Treatment order was randomly assigned. Pre- to post-procedure changes in pain intensity and peak frequency of electroencephalogram spectral analysis were compared between treatment conditions. Results: The active treatment condition (anodal tDCS over M1) but not sham treatment resulted in significant decreases in pain intensity. In addition, consistent with the study hypothesis, peak theta–alpha frequency (PTAF) assessed from an electrode placed over the site of stimulation increased more from pre- to post-session among participants in the active tDCS condition, relative to those in the sham tDCS condition. Moreover, we found a significant association between a decrease in pain intensity and an increase in PTAF at the stimulation site. Conclusions: The findings are consistent with the possibility that anodal tDCS over the left M1 may be effective, at least in part, because it results in an increase in M1 cortical excitability, perhaps due to a pain inhibitory effect of motor cortex stimulation that may influence the descending pain modulation system. Future research is needed to determine if there is a causal association between increased left anterior activity and pain reduction.

⇑ Corresponding author. Tel./fax: +6643347588. 1 2

E-mail address: [email protected] (P. Auvichayapat). Member of Noninvasive Brain Stimulation Research Group of Thailand. Consultant to Noninvasive Brain Stimulation Research Group of Thailand.

http://dx.doi.org/10.1016/j.clinph.2014.05.034 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

N. Ngernyam et al. / Clinical Neurophysiology 126 (2015) 382–390

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Significance: The results provide new findings regarding the effects of tDCS on neuropathic pain and brain oscillation changes. Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction Neuropathic pain (NP) is pain caused by a lesion in or disease of the somatosensory nervous system (Treede et al., 2008). About 50% of individuals with spinal cord injury (SCI) have NP and suffer from this pain (Finnerup, 2013). In addition, NP can have a significant negative impact on quality of life (Jensen et al., 2007). One factor that may contribute to SCI-related NP is an increase in the responsivity and excitability of dorsal horn neurons due to the loss (or suppression) of central inhibitory control mechanisms (Pasero, 2004). The most common treatments for SCI-related NP are pharmacological, and include antidepressants, antiepileptics, topical anesthetics, and opioids (Dworkin et al., 2007; Gordon and Love, 2004). Unfortunately, only about 40% of patients with NP from spinal cord injury obtain a favorable outcome from analgesic medications (Dworkin et al., 2007). Moreover, many analgesics have adverse effects, which cause many patients with SCI to discontinue treatment. Beyond pharmacological treatments, invasive motor cortex and spinal cord stimulation have shown some promise for treating NP (Nizard et al., 2012). Even larger response rates have been reported in patients who received a central lateral thalamotomy, which results in an increase in overall neuron excitability (of inhibitory neurons), as reflected by an increase in peak alpha spectrum (Sarnthein et al., 2006). However, these treatments are highly invasive and therefore have significant risk for serious adverse events. Non-invasive brain stimulation techniques, including transcranial direct current stimulation (tDCS), have received increasing attention as treatment options for SCI-related NP. tDCS involves the application of low current stimulation (often, 2 mA) via scalp electrodes to inject currents in the brain and modulate the level of cortical excitability (Nitsche et al., 2008). tDCS of the motor cortex (i.e., placement of the anode at or near M1or C3 site in the international 10-20 system) contralateral to the site of pain has demonstrated efficacy in a number of preliminary findings, and has been hypothesized to activate inhibitory systems that reduce nociceptive input into the thalamus (Mori et al., 2010; Fregni et al., 2006a; Fregni et al., 2006b; Boggio et al., 2009; Antal et al., 2010; Soler et al., 2010). However, whether tDCS operates via this or other possible mechanisms has not yet been confirmed. It should be noted, however, that not every study testing the efficacy of tDCS has found positive effects. In one recent study, for example, Wrigley and colleagues (2013) examined the efficacy of tDCS in 10 patients with SCI and longstanding NP (10 or more years) to determine the short-, medium-, and long-term efficacy of this treatment. In contrast to the results of a number of previous studies, cited above, they found tDCS focused over M1 was not associated with pain relief at any time point. The authors concluded that there are likely factors that moderate the efficacy of tDCS for SCI-related pain, and suggest that SCI duration may be one of those factors. Specifically, that tDCS may an effective analgesic only in individuals with relatively recent injuries; a hypothesis that is also consistent with a strong negative association (r = 0.66) found between pain relief and duration of pain reported by Fregni and colleagues (Fregni et al., 2006a). To the extent that tDCS operates via stimulation of inhibitory systems, it is also possible that it is only or mostly effective among individuals whose inhibitory system is relatively inactive at pretreatment.

One of the changes noted in neuronal activity following SCI is an increase in the proportion of thalamic cells firing in a theta frequency (4–8 Hz); a phenomenon that has also been observed in a number of NP conditions and has been labeled thalamocortical dysrhythmia (TCD) (Llina´s et al., 1999). This thalamic theta oscillation is thought to spread to other regions associated with pain processing, such as insular cortex, anterior cingulate cortex, and primary and secondary somatosensory cortices and in turn contribute to a decrease in peak alpha frequency (Boord et al., 2008). This process could potentially result in decreases in activity of the cortical inhibitory systems that play a role in suppressing the processing of nociception, and therefore contribute to an overall increase in the experience of pain. In support of this model, Sarnthein and colleagues used EEG spectral analysis to compare brain oscillations in patients with neurogenic pain relative to healthy controls and evaluate the impact of thalamotomy in the patients (Sarnthein et al., 2006). They found both (1) that the dominant peak in spectral power was shifted towards a lower frequency range in patients relative to controls and (2) an increase in peak alpha frequency (8–13 Hz) 3 and 12 months post-surgery in those patients who reported reductions in SCI-related NP following the surgical procedure (Sarnthein et al., 2006). In a subsequent study, Boord and colleagues examined the power of peak oscillations in the theta–alpha frequency (PTAF in the 4–13 Hz range) in a sample of individuals with SCI with and without NP, as well a control sample of otherwise healthy (nonSCI) individuals (Boord et al., 2008). They found that individuals with SCI and NP had PTAF values that were lower than the individuals with SCI who did not have pain, as well as individuals without either SCI or pain, in 14 electrode sites; these effects appeared strongest at the C3 site (in the 10-20 international system). These findings suggest an overall slowing of the peak frequency from an alpha towards the theta frequency range in individuals with SCIrelated NP, consistent with the putative presence of TCD in this population (Boord et al., 2008). Based on Boord and colleagues’ finding, we reasoned that one possible mechanism of tDCS is that it results in an increase in PTAF – reflecting an increase in (inhibitory) neuronal activity – following tDCS, and that a tDCS-related increase in PTAF would be associated with a reduction in pain among those who receive tDCS. In addition, based on the research cited previously suggesting that tDCS may be more effective in individuals with shorter pain or SCI duration than individuals with longer pain or SCI duration (Fregni et al., 2006a; Wrigley et al., 2013), we predicted larger pain reductions following a single tDCS session in individuals with shorter pain and SCI duration. Thus, we hypothesized: (1) a greater increase in PTAF pre- to post-tDCS stimulation among a group of individuals with SCI-related NP and who receive anodal tDCS over the M1 cortex, relative to a group who receive sham tDCS, (2) a negative association between change in PTAF and change in pain intensity (that is, those who report the greatest decrease in pain will evidence greater increases in PTAF) among those who receive active tDCS, and (3) larger effects of tDCS among individuals with shorter pain and SCI duration. Because we planned to assess EEG activity over multiple scalp sites, we would be able to determine if any treatment- or pain-related changes in PTAF are global (i.e., occur at multiple sites) or specific (i.e., to the site of tDCS stimulation, that is, C3 in the 10/20 system).

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2. Materials and Methods 2.1. Participant recruitment and informed consent Study participants were recruited via advertisements placed in the inpatient unit of medical rehabilitation, Faculty of Medicine, Khon Kaen University, Thailand. The study procedures were described to eligible patients who expressed an interest in participating in the study by clinic physicians. Study inclusion criteria included: (1) traumatic spinal cord injury due to accidents, gunshot, or diseases; (2) an average pain intensity rating measured by a numerical rating scale at baseline and before the tDCS session higher than or equal to 4 on a 0 (‘No pain’) and 10 (‘Worst pain that you could imagine’) scale; (3) pain problem refractory to medications, including tricyclic antidepressants, antiepileptic drugs, and/ or opioids (i.e., pain that does not respond to at least two of these drugs supplied in adequate dosages for 6 months); (4) no evidence of progressive neurological disease or other secondary conditions that could impact pain; and (5) not used alternative treatments for pain (herbal remedies and other alternative therapies) in the previous month. Study exclusion criteria include the following: (1) syringomyelia; (2) drug addiction; (3) current or history of drug abuse; (4) current psychiatric disorder such as schizophrenia (per medical record), depression (as indicated by a score of 16 or greater on the Beck Depression Inventory; Wongchai, 2003) or severe anxiety (as indicated by a score of 39 or lower on the Self-report rating scale of the Symptom Checklist-90; Department of Mental Health, 2011a); (5) significant cognitive deficits (as indicated by a score of 22 or lower on the Thai Mental State Examination; Department of Mental Health, 2011b); (6) history of loss of consciousness or post-traumatic amnesia at the time of injury; and (7) skull defects that would interfere with the EEG assessment. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Khon Kaen University (Identifier number: HE HE551002). Written informed consent was obtained from all participants before participation. 2.2. Study design The study was a randomized double-blind controlled placebo (sham tDCS) cross-over trial performed over 4 weeks consisting of: (1) 1 week baseline assessment; (2) a single session of with 2 mA active or sham tDCS (depending on order assignment) for 20 min; (3) 1 week of assessment and washout; (4) another week of baseline assessment; (5) another session of active or sham tDCS (depending on order assignment); and (5) a final week out outcome assessment. Thus, the study involved 4 weeks of participation. Just before the first treatment phase, participants were randomized to receive either active tDCS followed by sham tDCS, or sham tDCS stimulation followed by active tDCS in a 1:1 ratio using a computer generated list of random numbers in blocks of four randomizations (i.e., the order of stimulation was counter-balanced). Participants were asked to continue their routine analgesic medication regimen throughout the duration of the 4-week study. 2.3. Active and sham transcranial direct current stimulation tDCS was applied via 0.9% NaCl-soaked pair of surface sponge electrodes (35 cm2) and delivered through battery-driven power supply. The constant current stimulator had a maximum output of 10 mA (Soterixmedical, Model 1224-B, New York, USA). We planned to place the anode over C3 or C4 (EEG 10/20 system) to target the motor cortex (M1) contralateral to the most painful area of the body (i.e., left sided pain greater = right sided M1 stimulation) with 2 mA for 20 min, and the cathode (reference)

electrode on the shoulder contralateral to the anode (i.e., right sided stimulation = left shoulder). With this treatment, the current is gradually delivered by ramping up until reach to necessary current and is then ramped down after finishing stimulation. For patients with bilateral pain that was had the same intensity on both sides of the body, we planned to stimulate the dominant hemisphere (left for right-handed subjects, right for left-handed subjects) (Fregni et al., 2006a,b). However, as it turned out, all of the study participants were right handed and had bilateral pain. Therefore, all participants in the current study received left hemisphere stimulation. The tDCS device was designed to allow for masked (sham) stimulation. Specifically, the control switch was in front of the instrument, which was covered by an opaque adhesive during stimulation. The power indicator was on the front of the machine, which lit up during the time of stimulation both in active and sham tDCS conditions. However, in sham stimulation, the current was discontinued after 30 s while the power indicator remained on (Auvichayapat et al., 2013). 2.4. Measures Two primary outcome domains were assessed in this study: average pain intensity and PTAF at each electrode site. We also assessed adverse events associated with the active and sham tDCS procedures. 2.5. Pain intensity assessment Average pain intensity was assessed using 0–10 numerical rating scales (NRS) with the endpoints ‘‘No pain’’ and ‘‘The most possible pain.’’ Participants were asked to provide ratings of average pain in the past 24 h for four days during the first 1-week baseline period on a daily diary. These four ratings were averaged into a single composite score of baseline average pain intensity. In addition, to ensure that the participants had at least moderate pain before treatment, they were asked to rate their current pain before the tDCS session. They were also asked to rate pain immediately following the session, and to rate their 24-h recalled pain at 24-, and 48-h after the first stimulation (i.e., in the first two days of week 2). Pain assessment during weeks 3 and 4 mirrored these procedures (i.e., 4 ratings of 24-h recall average pain intensity during week three, averaged to create a composite score, ratings of current pain before and after the tDCS session, and two ratings 24- and 48-h after the second stimulation session, during week 4). 0–10 NRSs have a great deal of evidence supporting their reliability and validity as measures of pain intensity (Tan et al., 2004; Cleeland, 2009; Cleeland and Ryan, 1994) and are recommended as the best outcome measure in pain studies by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus group due to their many strengths and relatively few weaknesses (Dworkin et al., 2010). 2.6. Peak theta–alpha frequency (PTAF) Peak theta-alpha frequency (PTAF) was computed using EEG data collected and processed by trained staff. The study participants were seated or lying down comfortably in a quiet room during the assessment. They were asked to remain in a relaxed state but awake and avoid movement, and instructed to close their eyes and avoid mental activities. We acquired EEG data from the study participants using 19 channels EEG referenced to Cz, international 10-20 system of electrode placement (Neuvo, Compumedics, Australia with ProFusion EEG software). There are strengths and weaknesses associated with different choices for the reference electrode or electrodes; we

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chose to use Cz as the reference electrode in this study because we were interested in determining the replicability of the finding, reported by Boord and colleagues (Boord et al., 2008), that tDCS alters PTAF, and they used the Cz as the reference electrode in their study. EEG data were collected for 30 min with band pass filtered 0.1–70 Hz and sampled at 2048 Hz. EEG was recorded on the first day of the first week (i.e., one assessment in the first baseline week), immediately after the first stimulation session and again at 24- and 48 h after stimulation (i.e., 3 EEG assessments in week 2), and then again once during the second baseline week before the second stimulation, once immediately after the second stimulation and at 24- and 48 h after the second simulation in week 4 (i.e., a total of 8 EEG assessments, one before and three after each stimulation session). Electroopthalmogram (EOG) data were recorded from electrodes placed above and below the right eye and at the left and right outer canthi. Skin preparation reduced electrode impedance below 5 kO. To ensure that the participants remained awake throughout the session, they were asked to open and close their eyes at 60 s intervals. EEG data from sixty seconds of each EC intervals were deleted to eliminate the possibility of attentional transients due to initiation and termination of the eyes opening and closing stimulus. Three 10-min intervals of EC data were collected and subdivided into 2 s epochs. Artifacts were detected by visual inspection and independent component analysis (ICA). Epochs were multiplied by a Hanning window, transformed by a fast Fourier transform (FFT) with Welch method. The spectrum tested was frequency between theta–alpha range (4–13 Hz or TAF), consistent with the procedures used by Boord and colleagues (Boord et al., 2008). All EEG data were analyzed using MATLAB program by Mathwork (Natick, Massachusetts, USA). 2.7. Adverse events Study participants were asked to report any adverse events as well as other signs and symptoms at immediately post-treatment, and again at 24- and 48 h after each of the stimulation sessions. Participants were also closely observed by physicians during the study session.

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on pain (followed by Fisher’s LSD as appropriate), with the PTAF assessed at pre-stimulation, post-stimulation, and at 24- and 48 h post-stimulation as the dependent variables, and group assignment, treatment condition and time as the independent variables. The hypothesized associations between pre- to post-session changes in pain (mean difference) and (1) pre- to post-session changes in PTAF (mean difference), (2) pain duration, and (3) SCI duration were tested by computing Pearson correlation coefficients between these pain changes and the three predictors for each stimulation type (i.e., active and sham tDCS conditions). P values of < 0.05 were considered statistically significant. Analyses were completed using Stata software, version 10.0 (Stata Corp, College Station, Texas, USA). 3. Results 3.1. Baseline Demographic Data A total of 28 patients with SCI and NP were screened for possible participation between July 2011 and January 2012. Six participants were excluded; two because they had a history of loss of consciousness at the time of injury and four because they had a history of drug abuse. Twenty-two individuals met the study inclusion criteria. Twenty right-handed participants (mean age + SD = 44.5 + 9.16, 15 male and 5 female) with bilateral pain completed the entire study protocol. No participants were screened out of the study due to psychological factors (i.e., diagnosis of schizophrenia or meeting cut off scores for depression or anxiety) or cognitive dysfunction. Participants assigned to each condition order did not differ significantly with respect to age or sex. In addition, average pain intensity assessed during the first baseline period and before tDCS was not significantly different between the groups. Finally, no significant differences emerged between the participants assigned to each condition order in either baseline average pain intensity or PTAF scores. The diagnosis, etiologies, baseline pain intensity scores, current medication use, duration of spinal cord disease, duration of pain, spinal cord disease conditions are presented in Table 1.

2.8. Data analysis

3.2. Pain intensity

We first computed means and standard deviations of the demographic and outcome variables for descriptive purposes. Next, we compared the outcome measures obtained during the first baseline period (week 1) between study participants assigned to the two treatment orders (i.e., sham-active versus active-sham) using ttests, to ensure pre-stimulation equivalence between these groups. Results are presented as means and SEM. The study hypothesis regarding the effects of tDCS on pain intensity was tested using repeated measures analysis of variance (ANOVA), using the pain intensity scores obtained at pre-stimulation (composite of four 24-h recall ratings), immediately post-treatment (single rating of current pain), and at 24- and 48-h after stimulation (single ratings of 24-h recalled average pain) as the dependent variables. Group assignment (treatment order, that is, active-sham versus shamactive), treatment condition (active versus sham tDCS) and time (baseline, post-treatment, 24-h post-treatment and 48-h posttreatment) were the independent variables. We planned to use Fisher’s LSD to help interpret any significant main or interaction effects found. Furthermore, we also compared sham vs active tDCS differences by calculating the difference between pain intensity at baseline and each treatment time point, and comparing these difference scores using t-tests. The study hypothesis regarding the effects of tDCS on PTAF assessed from each electrode was tested using the same ANOVA procedures used to test the effects

Preliminary ANOVA analyses yielded no significant main or interaction effects involving condition order. Therefore, the data were collapsed across condition order, and this variable will not be considered further. The repeated-measures ANOVA with pain intensity as the dependent variable, condition (active versus sham tDCS) as a between-subjects independent variable, and time (preand post-session) as a within-subjects independent variable revealed no significant main effect for condition (F(1,38) = 0.01, p = 0.944) but there was significant main effect for time (F(1,38) = 19.02; p < 0.001), as well as a significant Condition  Time interaction (F(1,38) = 4.99; p = 0.031. In order to interpret the significant interaction, we performed post hoc analyses of the time factor for each treatment condition separately. These revealed a significant decrease in pain intensity from pre- to post-session for active tDCS treatment (0.800, 95% CI = 0.410 to 1.190; p < 0.001) but no statistically significant change in pain intensity for the sham condition (0.025, 95% CI = 0.049 to 0.549; p = 0.096) (see Fig. 1(a)). In addition, we compared the pre- to each post-treatment pain intensity difference scores between sham and active tDCS conditions using t-tests. These analyses indicated that the differences between the sham and active treatment conditions were significant immediately after stimulation (p = 0.043) and at 24 h post-treatment (0.041) (see Fig. 1(b)).

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Table 1 Patients baseline characteristics (n = 20). ASIA scale and level of SCI

Causes of SCI

Symptoms

Type of Pain

62

A, T11

MVA

b

AED, TCA

40 168

D, C3 A, T4

MVA MVA

b b

M M

AED AED, TCA

40 50

C, C3 D, C1

MVA MS

b, e b

40 47 56 40

M M M F

AED, TCA AED

61 9 45 55

A, T11 A, T3 C, L1 B, T7

MVA infection MVA MS

b b b, p b, p

10 11 12 13 14 15 16

46 41 30 47 47 59 33

M M M M M F F

AED, TCA Opioid AED AED, TCA AED AED

63 69 65 10 73 21 132

B, T6 A, T11 A, T6 A, T2 B, T6 C, T4 A, C6

falling shooting MVA MVA MVA infection MVA

b, b b b, b b, b,

17 18 19 20

26 45 55 50

M M M M

AED, TCA AED AED AED, TCA

26 60 19 25

A, T6 C, C4 C, C4 C, C5

falling MVA MVA MVA

b, p b b b

At and below Below At and below Below At and below Below Below Below At and below Below Below Below Below Below Below At and below Below Below Below Below

No.

Age

Sex

Present Medications

1

42

F

-

2 3

31 54

F M

4 5

52 49

6 7 8 9

Mean (SD) or rate (%)

Duration of SCI (month)

p

e p e, p

Duration of of Pain (month)

Average Pain Intensity at Baseline

60

4.00(0.00)

36 159

4.00(0.00) 8.75(0.50)

36 48

5.00(0.00) 5.00 (0.00)

59 7 36 48

5.25(0.50) 8.00(0.00) 4.00(0.00) 4.75(0.50)

60 67 64 7 70 18 120

5.00(0.00) 5.00(0.00) 6.00(0.00) 5.00(0.00) 5.00(0.00) 9.50(0.57) 7.00(0.00)

24 48 13 22

8.00(0.00) 7.25(0.50) 5.00(0.00) 4.00(0.00)

50.10(37.06)

5.77(1.69)

M:15 (75%) 44.50 (9.16)

F: 5 (25%)

54.65(38.66)

AED = antiepileptic drugs (e.g., valproate, gabapentin); Meds = medications; TCA = tricyclics antidepressants (e.g., amytriptiline); MS = Multiple Sclerosis; MVA = motor vehicle accident; b = burning; e = like electric shock; p = paresthesia.

3.3. Peak theta–alpha frequency As with the pain intensity variable, preliminary ANOVA analyses yielded no significant main or interaction effects involving condition order for the PTAF scores at any electrode sites. Therefore, the data were collapsed across condition order for all subsequent analyses. Each of 18 electrode sites was analyzed by a repeatedmeasures ANOVA to study the changes of PTAF compared between pre- and post-treatment sessions (immediately post treatment, 24 and 48 h) in which treatment condition (active versus sham tDCS) as a between-subjects independent variable, and time as a withinsubjects independent variable. The results revealed no significant main effect of condition at all electrode sites but there were significant main effects of time for 6 electrode sites: Fp1 (F(3, 38) = 4.03, p = 0.009), F3 (F(3, 38) = 5.57, p = 0.001), Fz (F(3, 38) = 7.29, p < 0.001), C3 (F(3,38) = 3.46; p = 0.019), P3 (F(3, 38) = 3.56, p = 0.017) and Pz (F(3, 38) = 6.28, p = 0.001) (Fig. 2), as well as a significant Condition x Time interactions for 4 sites: Fp1 (F(3, 38) = 3.37, p = 0.021), F3 (F(3, 38) = 2.77, p = 0.045, Fz (F(3, 38) = 7.19, p < 0.001), and C3(F(3,38) = 4.63; p = 0.004) (Table 2). In order to interpret the significant interactions, we performed post hoc analyses of the time factor for each treatment condition separately for Fp1, F3, Fz, and C3. The post hoc analyses of the time factor in the active tDCS condition participant revealed significant increases in PTAF at immediately post-treatment for all four electrode sites (Fp1 ( 0.590, 95% CI = 0.951 to 0.228, p = 0.002), F3 ( 0.653, 95% CI = 0.962 to 0.345, p < 0.001), Fz ( 0.809, 95% CI = 1.207 to 0.410, p < 0.001), and C3 ( 0.679, 95% CI = 1.064 to 0.294; p = 0.002). In addition, the significant increase at C3 maintained at both the 24 h ( 0.478, 95% CI = 0.923 to 0.033; p = 0.037) and 48 h ( 0.523, 95% CI = 0.956 to 0.090, p = 0.021) assessment points (Table 2). For the sham condition, there were no significant changes in PTAF

for any electrode, including the four that showed significant Condition  Time interaction effects (Fig. 2). 3.4. Correlation between change in pain intensity and change in PTAF No significant associations were found between baseline to immediately post-treatment changes in pain intensity and change in PTAF measures for any electrode sites across both treatment conditions or for the sham treatment condition. Only one significant association emerged for participants in the active tDCS condition; that between an increase in PTAF and a decrease in pain intensity from pre-treatment to immediately post-treatment at C3 (r = 0.63, p = 0.003; n = 20) (Fig. 3). 3.5. Association between reduced pain intensity and both pain and SCI duration Neither of the associations between response to active or sham tDCS treatment were significantly associated with pain duration; the rs for pre- to post-session change in pain intensity and duration and response to active and sham tDCS were 0.22 (p = 0.332) and 0.44 (p = 0.051), respectively. Similarly, the associations between response to active and sham tDCS treatment were not significantly associated with duration of spinal cord injury; the rs for pre- to post-session change in pain intensity and duration and response to active and sham tDCS were 0.24 (p = 0.305) and 0.42 (p = 0.065), respectively. It was interesting to note, however, that the directions of the associations were different for the two treatment conditions; greater SCI and pain duration were (nonsignificantly) associated with more pain reduction following active tDCS, while shorter SCI and pain duration were (non-significantly) associated with more pain reduction following sham tDCS.

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Pain intensity

6

5

4 Baseline Before Immediately 24 hours 48 hours

Pain intensity

1.0

0.5

0.0

-0.5

Fig. 1. (a) Effect of treatment conditions on pain intensity (average of NRS intensity ratings). Data are presented as mean of NRS at baseline and at before tDCS, immediately post-treatment, 24, and 48 h follow-up. Vertical lines represent SEM. #p < 0.001 a significant difference in pain intensity from pre- to post-treatment at immediately for participants in the active tDCS condition but no statistically significant change in pain intensity for participants in the sham condition. (b) Mean differences in pain reduction between sham vs active tDCS treatment at each time points (immediately post-treatment, 24 and 48 h). Vertical lines represent SEM. ⁄p < 0.05 significant differences in pain intensity of sham vs active tDCS condition at immediately post-treatment and 24 h.

3.6. Adverse events With respect to adverse effects, all of the study participants tolerated the stimulation procedures well. However, seven participants evidenced erythematous rash under the cathode (negative) electrode in the active tDCS condition. 4. Discussion Consistent with the study hypotheses, we found that a single stimulation of anodal tDCS over the motor cortex (C3 in the international 10/20 system) resulted in a significant decrease in pain intensity and an increase in PTAF from pre- to post-stimulation, relative to sham tDCS, in a sample of right-handed individuals with bilateral NP associated with SCI. Also as hypothesized, we found a significant association between a decrease in pain intensity and an increase in PTAF in those who received active tDCS treatment, although this association emerged only at the stimulation site (C3). Inconsistent with the second study hypothesis, however, we did not find a significant association between response to tDCS stimulation and duration of pain, and also of spinal cord injury; if anything, the pattern of (non-significant) findings were in the direction opposite that predicted. The findings contribute to our understanding of the effects (and potential moderators) of tDCS, and have important implications for understanding the effect of active tDCS on SCI-related NP.

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The findings demonstrating an increase in PTAF from pre- to immediately post anodal tDCS stimulation at the site of stimulation (C3) as well as three nearby the maintenance of this change in PTAF through 48 h post-stimulation at C3 provides preliminary evidence for a possible specific mechanism of effect of tDCS on a measure previously linked to pain intensity in individuals with SCI. This finding is also consistent with those from a study in a sample of healthy subjects that found anodal tDCS over left primary motor cortex to increase intrahemispheric connectivity across multiple bandwidths (i.e., delta, theta, alpha, and high gamma; Polanía et al., 2011) as well as another study that found another brain stimulation technique (rTMS) to increase peak of alpha frequency (PAF) at F3, F4, C3, T3, T4, Fz and Cz (Okamura et al., 2001). Although additional replication of these findings are needed to confirm their reliability, if replicated in additional samples, they would support a conclusion that non-invasive stimulation techniques (specifically, tDCS and rTMS) have (activating) neurophysilogical effects that can last beyond the stimulation sessions, supporting their potential for treating conditions – like chronic pain – that are linked to cortical processes (Apkarian, 2013; Farmer et al., 2012). Our findings are also consistent with the hypothesis that increasing cortical activity in left anterior regions (as reflected by an increase in PTAF, perhaps in particular as assessed over the motor cortex) may be associated with pain relief in individuals with SCI and NP. Not only did we find that anodal tDCS over the motor cortex was more effective (for reducing pain) than sham tDCS, but we found that an increase in PTAF specifically at the site of stimulation may be associated with pain relief from pre- to postactive tDCS. This finding is consistent with Llina´s thalamocortical dysrhythmia hypothesis, suggesting that a decrease in activity in frontal inhibitory neurons may contribute to NP, at least in individuals with SCI and chronic pain (Llina´s et al., 1999). However, the present findings do not confirm a causal role for lower PTAF in producing pain, or higher PTAF in relieving pain. Whether or not the associations found here are due to PTAF somehow directly influencing pain, or merely reflect some other as-yet unidentified causal process (e.g., a third variable influencing both PTAF and pain intensity), will require additional research. Nevertheless, it is clear that thalamic activity plays a central role in signal transmission (Hamada and Wada, 1998), and influencing this activity via stimulating motor cortex has been proposed by many investigators as a potential mechanism of tDCS (Mori et al., 2010; Fregni et al., 2006a; Wrigley et al., 2013; Boggio et al., 2009; Antal et al., 2010; Soler et al., 2010). Our findings showed that the EEG power spectra changed both at the stimulated site (C3) as well as at three additional left anterior electrode sites, similar to Polania and colleague’s (2011) finding using tDCS coupled EEG in healthy subjects. These findings suggest that tDCS may influence activity in areas related pain processing areas beyond just the thalamus. The functional relationship between motor cortex and areas related to pain processing area can occur via both direct and indirect pathways (Vaseghi et al., 2014). Specifically, increased motor cortex activation (reflecting by increased PTAF) via tDCS can potentially influence inhibitory neurons in both adjacent and distant brain areas. For example, tDCS over motor cortex may increase the activity of inhibitory neurons in dorsal lateral prefrontal cortex via direct connections between these areas (Hasan et al., 2013), and an increase in frontal inhibitory systems could then exert an active control on pain perception (Lorenz et al., 2003). Alternatively, studies using direct motor cortex stimulation suggest that this stimulation could directly induce inhibition of regions of brain involved in emotional response of pain such as anterior cingulate cortex (Leung et al., 2009), resulting in a reduction in both the affective and emotional pain in pain processing area. However, more research is needed, perhaps using

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Fig. 2. Changed PTAF of 19 electrode sites (referenced to Cz) after stimulation by active or sham tDCS over motor cortex (C3) during different times compared between 2 conditions showing significant increase with main effect of time for 5 EEG sites in active tDCS condition: Fp1, F3, Fz, P3 at immediately post treatment and C3 at immediately post treatment, 24 and 48 h and also a significant decrease of Pz site at 24 and 48 h. There were no significant differences at any time points in sham condition. (a) PTAF at immediately post treatment, 24 and 48 h compared with baseline in active tDCS condition (b) PTAF at immediately post treatment, 24 and 48 h compared with baseline in sham condition. (Red = increase; Blue = decrease; White = no changes; ⁄ represents significant different main effect of time; ⁄p < 0.05; ⁄⁄p < 0.01; ⁄⁄⁄p < 0.001). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) Table 2 PTAF score of EEG recorded at different electrode sites and significant differences compared with baseline in the active tDCS (anodal stimulation over the motor cortex) and sham conditions. Active condition

Sham condition

Remark

Channel

Baseline

Immediately

24 h

48 h

Baseline

Immediately

24 h

48 h

Fp1 Fp2 F7 F3 Fz F4 F8 T3 C3 C4 T4 T5 P3 Pz P4 T6 O1 O2

8.21 8.53 8.58 7.64 7.99 8.24 9.07 9.05 8.99 9.24 9.14 8.93 8.98 9.11 9.04 9.15 9.00 9.03

9.33⁄⁄ 8.57 8.93 8.73⁄⁄⁄ 9.21⁄⁄⁄ 9.08 8.90 9.77 9.67⁄⁄ 8.85 8.46 8.97 9.59⁄⁄ 9.46 9.34 9.34 8.94 9.47

8.08 8.43 8.70 8.07 7.98 7.98 8.61 9.26 9.47⁄ 8.27 9.02 9.44 9.38 8.82⁄ 9.05 9.44 9.01 8.83

8.47 8.57 8.30 8.21 7.77 7.88 8.98 9.59 9.51⁄ 9.11 9.44 9.47 9.48 8.85⁄ 8.72 9.60 9.39 9.54

8.26 8.55 8.45 7.90 7.92 8.06 9.31 8.97 8.97 9.34 9.16 9.08 8.86 9.27 9.19 9.05 9.11 9.09

8.32 8.54 8.48 8.09 8.12 8.22 9.26 9.01 8.93 9.20 9.10 9.08 9.17 9.21 9.20 9.07 8.98 9.12

8.26 8.65 8.77 8.11 7.99 8.26 9.16 8.97 8.92 8.96 9.00 9.12 9.05 9.08 9.19 9.09 9.08 9.06

8.38 8.84 8.59 8.16 7.93 8.44 9.29 9.02 8.92 9.05 8.99 8.99 8.93 8.98 9.02 9.01 9.17 8.97

 

      

  

Significant difference when compared with baseline indicated by ⁄p < 0.05; ⁄⁄p < 0.01; ⁄⁄⁄p < 0.001. Significant Condition  Time interactions indicated by  p < 0.05;   p < 0.01;    p < 0.001.

procedures that couple tDCS with other brain imaging techniques such as functional Magnetic Resonance Imaging (fMRI) or Positron Emission Topography (PET), to test for associations between activity in the primary motor cortex, thalamus and pain processing areas, which could provide evidence confirming or disconfirmation the impact of tDCS-induced alterations on cortico-cortical or cortico-subcortical network functions (Polanía et al., 2012; Yoon et al., 2014).

Finally, investigators have speculated that some of the inconsistencies in previous regarding the analgesic effects of tDCS may be related to pain or SCI duration, and hypothesized that tDCS may be more effective for individuals with more recent pain or SCI onset (Wrigley et al., 2013). These hypotheses were not supported in the current study. Given the variability of the impact of tDCS on pain in individuals with SCI, both between studies and within studies, it remains possible that other factors moderating the impact of

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found successful blinding with sham tDCS (Wrigley et al., 2013). Still, we did not evaluate the success of blinding in this study, so it remains possible that potential unblinding might have contributed to the beneficial effects found for the active tDCS treatment on pain intensity. However, we think it unlikely that unblinding could explain the effects of tDCS we found on PTAF.

Decreased pain intensity at immediately post treatment

Change of PTAF at immediately post treatment

1

0

2

389

3

6. Conclusions -1

Despite the study’s limitations, the findings indicate that a single stimulation session of anodal tDCS at left motor area (in a group of right handed individuals with SCI and bilateral pain) can result in a significant reduction in SCI-related NP, and that increases in PTAF at the site of stimulation may reflect possible mechanisms of efficacy of this treatment. Future research is needed to determine the replicability of these findings in other samples of individuals with NP conditions.

-2

-3 Fig. 3. Correlation between pain reduction and change in PTAF at C3 (r = p = 0.003; n = 20).

0.63,

Acknowledgements tDCS might be identified. One clear possibility, based on our findings, is the extent to which an individual’s motor cortex is relatively inactive at baseline; presumably if tDCS is effective due to motor cortex activation, individuals with relatively low motor cortex activity at baseline might have the most to gain from this treatment. Other possible moderators could include type of pain (not only neuropathic versus nociceptive, but types of neuropathic pain, such as central versus peripheral) and the temporal quality of pain (e.g., intermittent versus continuous). Research examining these possible moderating factors is warranted. 5. Study limitations A number of factors, such as medications and sleep quality can impact EEG measures, including PTAF. We did not assess or control for these factors in the current study. However, give that these factors can add potential error to measurement, they would have attenuated the associations found. The fact that we found significant effects on PTAF and also a significant association between change in PTAF and change in pain despite the lack of control for mediation use and sleep quality provides additional support for the potential strength and reliability of these findings. However, future research should assess and control for these possible confounds when possible. In addition, standard treatment using tDCS for chronic pain involves at least five sessions of stimulation (e.g., Mori et al., 2010; Fregni et al., 2006a; Fregni et al., 2006b); in this study, we only examined the effects of a single session of tDCS on pain and PTAF measures. Thus, the current findings cannot be used to draw conclusions regarding the effects of a full course of tDCS on pain, PTAF, or their association. An important next step would be to examine the impact (and duration) of 5 or more sessions of tDCS on both pain and PTAF. A third limitation is that, although we used standard procedures (i.e., the international 10-20 system) for tDCS electrode placement, we did not confirm that the stimulation electrode was directly over the motor cortex and, using for example transcranial magnetic stimulation (TMS) to locate motor responses (Sparing et al., 2008; Herwig et al., 2003). Given the size of the electrodes (35 cm2), tDCS procedures likely result in more generalized (hemi-cortical) stimulation than very specific stimulation. Thus, we cannot confirm that the M1 cortex (and only the M1 cortex) was stimulated in this study, and therefore whether M1 stimulation (versus other areas) explain or underlie the benefits found. Finally, since the current study was designed and completed, investigators have noted that unblinding can occur with sham tDCS (O’Connell et al., 2012), although other researchers have

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